HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information
needed to use ALPHAGAN® P safely and effectively.
See full prescribing information for ALPHAGAN® P.
ALPHAGAN® P (brimonidine tartrate ophthalmic
solution) 0.1% and 0.15%
Initial U.S. Approval: 1996
___________
___________
INDICATIONS AND USAGE
ALPHAGAN® P is an alpha adrenergic receptor agonist
indicated for the reduction of elevated intraocular pressure
(IOP) in patients with open-angle glaucoma or ocular
hypertension. (1)
________
________
DOSAGE AND ADMINISTRATION
One drop in the affected eye(s), three times daily,
approximately 8 hours apart. (2)
_______
_______
DOSAGE FORMS AND STRENGTHS
Solution containing 1 or 1.5 mg/mL brimonidine tartrate. (3)
___________
______________
CONTRAINDICATIONS
Neonates and infants (under the age of 2 years). (4.1)
________
________
WARNINGS AND PRECAUTIONS
Potentiation of vascular insufficiency. (5.1)
___________
___________
ADVERSE REACTIONS
Most common adverse reactions occurring in
approximately 5% to 20% of patients receiving brimonidine
ophthalmic solution (0.1%-0.2%) included allergic
conjunctivitis, burning sensation, conjunctival folliculosis,
conjunctival hyperemia, eye pruritus, hypertension, ocular
allergic reaction, oral dryness, and visual disturbance. (6.1)
To report SUSPECTED ADVERSE REACTIONS,
contact Allergan at 1-800-433-8871 or the FDA at 1-800FDA-1088 or www.fda.gov/medwatch.
_____________
_____________
DRUG INTERACTIONS
 Antihypertensives/cardiac glycosides may lower blood
pressure. (7.1)
 Use with CNS depressants may result in an additive or
potentiating effect. (7.2)
 Tricyclic antidepressants may potentially blunt the
hypotensive effect of systemic clonidine. (7.3)
 Monoamine oxidase inhibitors may result in increased
hypotension. (7.4)
________
________
USE IN SPECIFIC POPULATIONS
Use with caution in children ≥ 2 years of age. (8.4)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 09/2013
FULL PRESCRIBING INFORMATION:
CONTENTS*
1
INDICATIONS AND USAGE
2
DOSAGE AND ADMINISTRATION
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
4.1
Neonates and Infants (under the age of 2
years)
4.2
Hypersensitivity Reactions
5
WARNINGS AND PRECAUTIONS
5.1
Potentiation of Vascular Insufficiency
5.2
Severe Cardiovascular Disease
5.3
Contamination of Topical Ophthalmic
Products After Use
6
ADVERSE REACTIONS
6.1
Clinical Studies Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Antihypertensives/Cardiac Glycosides
7.2
CNS Depressants
7.3
Tricyclic Antidepressants
7.4
Monoamine Oxidase Inhibitors
8
10
11
12
13
14
16
17
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Special Populations
OVERDOSAGE
DESCRIPTION
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.3
Pharmacokinetics
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment
of Fertility
CLINICAL STUDIES
HOW SUPPLIED/STORAGE AND
HANDLING
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing
information are not listed.
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
ALPHAGAN® P (brimonidine tartrate ophthalmic solution) 0.1% or 0.15% is an alpha adrenergic receptor
agonist indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma
or ocular hypertension.
2
DOSAGE AND ADMINISTRATION
The recommended dose is one drop of ALPHAGAN® P in the affected eye(s) three times daily, approximately
8 hours apart. ALPHAGAN® P ophthalmic solution may be used concomitantly with other topical ophthalmic
drug products to lower intraocular pressure. If more than one topical ophthalmic product is to be used, the
different products should be instilled at least 5 minutes apart.
3
DOSAGE FORMS AND STRENGTHS
Solution containing 1 mg/mL or 1.5 mg/mL brimonidine tartrate.
4
CONTRAINDICATIONS
4.1
Neonates and Infants (under the age of 2 years)
ALPHAGAN® P is contraindicated in neonates and infants (under the age of 2 years).
4.2
Hypersensitivity Reactions
ALPHAGAN® P is contraindicated in patients who have exhibited a hypersensitivity reaction to any
component of this medication in the past.
5
WARNINGS AND PRECAUTIONS
5.1
Potentiation of Vascular Insufficiency
ALPHAGAN® P may potentiate syndromes associated with vascular insufficiency. ALPHAGAN® P should be
used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon,
orthostatic hypotension, or thromboangiitis obliterans.
5.2
Severe Cardiovascular Disease
Although brimonidine tartrate ophthalmic solution had minimal effect on the blood pressure of patients in
clinical studies, caution should be exercised in treating patients with severe cardiovascular disease.
5.3
Contamination of Topical Ophthalmic Products After Use
There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical
ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had
a concurrent corneal disease or a disruption of the ocular epithelial surface (see PATIENT COUNSELING
INFORMATION, 17).
6
ADVERSE REACTIONS
6.1
Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the
clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not
reflect the rates observed in practice.
Adverse reactions occurring in approximately 10-20% of the subjects receiving brimonidine ophthalmic
solution (0.1-0.2%) included: allergic conjunctivitis, conjunctival hyperemia, and eye pruritus. Adverse
reactions occurring in approximately 5-9% included: burning sensation, conjunctival folliculosis, hypertension,
ocular allergic reaction, oral dryness, and visual disturbance.
Adverse reactions occurring in approximately 1-4% of the subjects receiving brimonidine ophthalmic solution
(0.1-0.2%) included: abnormal taste, allergic reaction, asthenia, blepharitis, blepharoconjunctivitis, blurred
vision, bronchitis, cataract, conjunctival edema, conjunctival hemorrhage, conjunctivitis, cough, dizziness,
dyspepsia, dyspnea, epiphora, eye discharge, eye dryness, eye irritation, eye pain, eyelid edema, eyelid
erythema, fatigue, flu syndrome, follicular conjunctivitis, foreign body sensation, gastrointestinal disorder,
headache, hypercholesterolemia, hypotension, infection (primarily colds and respiratory infections), insomnia,
keratitis, lid disorder, pharyngitis, photophobia, rash, rhinitis, sinus infection, sinusitis, somnolence, stinging,
superficial punctate keratopathy, tearing, visual field defect, vitreous detachment, vitreous disorder, vitreous
floaters, and worsened visual acuity.
The following reactions were reported in less than 1% of subjects: corneal erosion, hordeolum, nasal dryness,
and taste perversion.
6.2
Postmarketing Experience
The following reactions have been identified during postmarketing use of brimonidine tartrate ophthalmic
solutions in clinical practice. Because they are reported voluntarily from a population of unknown size,
estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their
seriousness, frequency of reporting, possible causal connection to brimonidine tartrate ophthalmic solutions, or
a combination of these factors, include: bradycardia, depression, hypersensitivity, iritis, keratoconjunctivitis
sicca, miosis, nausea, skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), syncope, and
tachycardia. Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory
depression, and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions.
7
DRUG INTERACTIONS
7.1
Antihypertensives/Cardiac Glycosides
Because ALPHAGAN® P may reduce blood pressure, caution in using drugs such as antihypertensives and/or
cardiac glycosides with ALPHAGAN® P is advised.
7.2
CNS Depressants
Although specific drug interaction studies have not been conducted with ALPHAGAN® P, the possibility of an
additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anesthetics)
should be considered.
7.3
Tricyclic Antidepressants
Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not
known whether the concurrent use of these agents with ALPHAGAN® P in humans can lead to resulting
interference with the IOP lowering effect. Caution is advised in patients taking tricyclic antidepressants which
can affect the metabolism and uptake of circulating amines.
7.4
Monoamine Oxidase Inhibitors
Monoamine oxidase (MAO) inhibitors may theoretically interfere with the metabolism of brimonidine and
potentially result in an increased systemic side-effect such as hypotension. Caution is advised in patients taking
MAO inhibitors which can affect the metabolism and uptake of circulating amines.
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category B: Teratogenicity studies have been performed in animals.
Brimonidine tartrate was not teratogenic when given orally during gestation days 6 through 15 in rats and days
6 through 18 in rabbits. The highest doses of brimonidine tartrate in rats (2.5 mg/kg/day) and rabbits (5.0
mg/kg/day) achieved AUC exposure values 360- and 20-fold higher, or 260- and 15-fold higher, respectively,
than similar values estimated in humans treated with ALPHAGAN® P 0.1% or 0.15%, 1 drop in both eyes
three times daily.
There are no adequate and well-controlled studies in pregnant women; however, in animal studies, brimonidine
crossed the placenta and entered into the fetal circulation to a limited extent. Because animal reproduction
studies are not always predictive of human response, ALPHAGAN® P should be used during pregnancy only if
the potential benefit to the mother justifies the potential risk to the fetus.
8.3
Nursing Mothers
It is not known whether brimonidine tartrate is excreted in human milk, although in animal studies, brimonidine
tartrate has been shown to be excreted in breast milk. Because of the potential for serious adverse reactions
from ALPHAGAN® P in nursing infants, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother.
8.4
Pediatric Use
ALPHAGAN® P is contraindicated in children under the age of 2 years (see CONTRAINDICATIONS, 4.1).
During postmarketing surveillance, apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy,
pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine. The safety
and effectiveness of brimonidine tartrate have not been studied in children below the age of 2 years.
In a well-controlled clinical study conducted in pediatric glaucoma patients (ages 2 to 7 years) the most
commonly observed adverse reactions with brimonidine tartrate ophthalmic solution 0.2% dosed three times
daily were somnolence (50-83% in patients ages 2 to 6 years) and decreased alertness. In pediatric patients 7
years of age (>20 kg), somnolence appears to occur less frequently (25%). Approximately 16% of patients on
brimonidine tartrate ophthalmic solution discontinued from the study due to somnolence.
8.5
Geriatric Use
No overall differences in safety or effectiveness have been observed between elderly and other adult patients.
8.6
Special Populations
ALPHAGAN® P has not been studied in patients with hepatic impairment.
ALPHAGAN® P has not been studied in patients with renal impairment. The effect of dialysis on brimonidine
pharmacokinetics in patients with renal failure is not known.
10
OVERDOSAGE
Very limited information exists on accidental ingestion of brimonidine in adults; the only adverse reaction
reported to date has been hypotension. Symptoms of brimonidine overdose have been reported in neonates,
infants, and children receiving ALPHAGAN® P as part of medical treatment of congenital glaucoma or by
accidental oral ingestion (see USE IN SPECIFIC POPULATIONS, 8.4). Treatment of an oral overdose
includes supportive and symptomatic therapy; a patent airway should be maintained.
11
DESCRIPTION
ALPHAGAN® P (brimonidine tartrate ophthalmic solution) 0.1% or 0.15%, sterile, is a relatively selective
alpha-2 adrenergic receptor agonist (topical intraocular pressure lowering agent).
The structural formula of brimonidine tartrate is:
5-Bromo-6-(2-imidazolidinylideneamino) quinoxaline L-tartrate; MW= 442.24
In solution, ALPHAGAN® P (brimonidine tartrate ophthalmic solution) has a clear, greenish-yellow color. It
has an osmolality of 250-350 mOsmol/kg and a pH of 7.4-8.0 (0.1%) or 6.9-7.4 (0.15%).
Brimonidine tartrate appears as an off-white to pale-yellow powder and is soluble in both water (0.6 mg/mL)
and in the product vehicle (1.4 mg/mL) at pH 7.7.
Each mL of ALPHAGAN® P contains the active ingredient brimonidine tartrate 0.1% (1 mg/mL) or 0.15% (1.5
mg/mL) with the inactive ingredients sodium carboxymethylcellulose; sodium borate; boric acid; sodium
chloride; potassium chloride; calcium chloride; magnesium chloride; PURITE® 0.005% (0.05 mg/mL) as a
preservative; purified water; and hydrochloric acid and/or sodium hydroxide to adjust pH.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
ALPHAGAN® P is a relatively selective alpha-2 adrenergic receptor agonist with a peak ocular hypotensive
effect occurring at two hours post-dosing.
Fluorophotometric studies in animals and humans suggest that brimonidine tartrate has a dual mechanism of
action by reducing aqueous humor production and increasing uveoscleral outflow.
12.3 Pharmacokinetics
Absorption
After ocular administration of either a 0.1% or 0.2% solution, plasma concentrations peaked within 0.5 to 2.5
hours and declined with a systemic half-life of approximately 2 hours.
Distribution
The protein binding of brimonidine has not been studied.
Metabolism
In humans, brimonidine is extensively metabolized by the liver.
Excretion
Urinary excretion is the major route of elimination of brimonidine and its metabolites. Approximately 87% of
an orally-administered radioactive dose of brimonidine was eliminated within 120 hours, with 74% found in the
urine.
13
13.1
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
No compound-related carcinogenic effects were observed in either mice or rats following a 21-month and 24month study, respectively. In these studies, dietary administration of brimonidine tartrate at doses up to 2.5
mg/kg/day in mice and 1 mg/kg/day in rats achieved 150 and 120 times or 90 and 80 times, respectively, the
plasma Cmax drug concentration in humans treated with one drop of ALPHAGAN® P 0.1% or 0.15% into both
eyes 3 times per day, the recommended daily human dose.
Brimonidine tartrate was not mutagenic or clastogenic in a series of in vitro and in vivo studies including the
Ames bacterial reversion test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, and three
in vivo studies in CD-1 mice: a host-mediated assay, cytogenetic study, and dominant lethal assay.
Reproduction and fertility studies in rats with brimonidine tartrate demonstrated no adverse effect on male or
female fertility at doses which achieve up to approximately 125 and 90 times the systemic exposure following
the maximum recommended human ophthalmic dose of ALPHAGAN® P 0.1% or 0.15%, respectively.
14
CLINICAL STUDIES
Elevated IOP presents a major risk factor in glaucomatous field loss. The higher the level of IOP, the greater the
likelihood of optic nerve damage and visual field loss. Brimonidine tartrate has the action of lowering
intraocular pressure with minimal effect on cardiovascular and pulmonary parameters.
Clinical studies were conducted to evaluate the safety, efficacy, and acceptability of ALPHAGAN® P
(brimonidine tartrate ophthalmic solution) 0.15% compared with ALPHAGAN® administered three-times-daily
in patients with open-angle glaucoma or ocular hypertension. Those results indicated that ALPHAGAN® P
(brimonidine tartrate ophthalmic solution) 0.15% is comparable in IOP lowering effect to ALPHAGAN®
(brimonidine tartrate ophthalmic solution) 0.2%, and effectively lowers IOP in patients with open-angle
glaucoma or ocular hypertension by approximately 2-6 mmHg.
A clinical study was conducted to evaluate the safety, efficacy, and acceptability of ALPHAGAN® P
(brimonidine tartrate ophthalmic solution) 0.1% compared with ALPHAGAN® administered three-times-daily
in patients with open-angle glaucoma or ocular hypertension. Those results indicated that ALPHAGAN® P
(brimonidine tartrate ophthalmic solution) 0.1% is equivalent in IOP lowering effect to ALPHAGAN®
(brimonidine tartrate ophthalmic solution) 0.2%, and effectively lowers IOP in patients with open-angle
glaucoma or ocular hypertension by approximately 2-6 mmHg.
16
HOW SUPPLIED/STORAGE AND HANDLING
ALPHAGAN® P is supplied sterile, in teal opaque plastic LDPE bottles and tips, with purple high impact
polystyrene (HIPS) caps as follows:
0.1%
5 mL in 10 mL bottle
NDC 0023-9321-05
10 mL in 10 mL bottle
NDC 0023-9321-10
15 mL in 15 mL bottle
NDC 0023-9321-15
0.15%
5 mL in 10 mL bottle
10 mL in 10 mL bottle
15 mL in 15 mL bottle
NDC 0023-9177-05
NDC 0023-9177-10
NDC 0023-9177-15
Storage: Store at 15o-25oC (59o-77oF).
17
PATIENT COUNSELING INFORMATION
Patients should be instructed that ocular solutions, if handled improperly or if the tip of the dispensing container
contacts the eye or surrounding structures, can become contaminated by common bacteria known to cause
ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated
solutions (see WARNINGS AND PRECAUTIONS, 5.3). Always replace the cap after using. If solution
changes color or becomes cloudy, do not use. Do not use the product after the expiration date marked on the
bottle.
Patients also should be advised that if they have ocular surgery or develop an intercurrent ocular condition (e.g.,
trauma or infection), they should immediately seek their physician's advice concerning the continued use of the
present multidose container.
If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes
apart.
As with other similar medications, ALPHAGAN® P may cause fatigue and/or drowsiness in some patients.
Patients who engage in hazardous activities should be cautioned of the potential for a decrease in mental
alertness.
© 2013 Allergan, Inc.
Irvine, CA 92612, U.S.A.
®
marks owned by Allergan, Inc.
Patented. See: www.allergan.com/products/patent_notices
Made in the U.S.A.
71816US16